Methods for Treating Ascites

ABSTRACT

The invention relates to the treatment of ascites, and especially refractory ascites, with an orally bioavailable prodrug of dopamine. A preferred prodrug of dopamine is docarpamine. The invention preferably contemplates intermittent dosing, wherein a treatment period is followed by an off-treatment period, which is followed by another treatment period.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application Ser.No. 63/139,616, filed Jan. 20, 2021.

BACKGROUND OF THE INVENTION

Ascites is a pathologic accumulation of fluid within the peritonealcavity. It is most commonly associated with cirrhosis of the liver (84%of cases), but is also seen with some forms of cancer (6% of cases, mostfrequently associated with breast, bronchus, ovary, stomach, pancreasand colon cancer), heart failure (3%), tuberculosis (1%), dialysis,pancreatic disease and other conditions (Runyon 1992).

Refractory Ascites (RA) is a serious medical complication of livercirrhosis that occurs when ascites can no longer be treated withdiuretics and salt restriction, and requires additional and repeatedclinical intervention, including large volume paracentesis. It isassociated with a significant shortening of life expectancy, increaseduse of medical resources, and ultimately is only curable by livertransplantation.

The pathophysiology underlying cirrhotic ascites is related to acombination of two pathogenetic mechanisms: portal hypertension andrenal sodium retention as a consequence of arterial underfilling. Anincreased resistance to portal flow at the sinusoidal level leads to thedevelopment of sinusoidal portal hypertension and the backwardtransmission of this increased pressure into splanchnic capillaries. Theresult is that the excess of fluid preferentially localizes in theperitoneal cavity. A decrease in effective arterial blood volume due tovasodilator factors such as nitric oxide leads to the activation ofanti-natriuretic and vasoconstrictor factors (mainlyrenin-angiotensin-aldosterone system, sympathetic nervous system andarginine vasopressin) with subsequent sodium retention. The mainconsequence of these hemodynamic and renal alterations is a continuousescape of fluid from the hepatic sinusoids and from the splanchniccapillaries into the interstitial space. This spillover is initiallycompensated by an increased return of fluids to the systemic circulationthrough the lymphatic system and the thoracic duct. However, ascirrhosis progresses, the escape of fluids overcomes the lymphaticreturn, leading to progressive accumulation of fluid directly into theperitoneal cavity. This is followed by a further activation of the renalmechanisms of sodium and water re-absorption that is crucial toperpetuate ascites formation (Salerno 2010, Pose 2017).

Within 10 years after the diagnosis of compensated cirrhosis, about 50percent of patients will have developed ascites (Gines 1987). Ascites isnormally treated with a combination of diuretics (with spironolactoneand furosemide most commonly used) and restricted salt intake. With thisregimen ascites can be managed in the majority of patients. Patientswith cirrhosis and a first onset of ascites have a probability ofsurvival of 85% during the first year and 56% at 5 years without livertransplantation (Pose 2017).

Ascites deteriorates to RA via the following pathophysiologicalmechanism. The severity of renal sodium retention increases throughoutthe natural history of cirrhosis, because of the progression of systemicand portal hemodynamic abnormalities and the associated activation ofneuro-humoral vasoactive systems leading to avid renal reabsorption ofsodium and water. At the same time, renal perfusion and glomerularfiltration rate progressively decline. As a result, sodium re-absorptionat the proximal convoluted tubule markedly increases and its delivery todistal segments of the nephron is markedly reduced. Thus, renal sodiumretention mainly occurs proximally to the site of action of bothanti-mineralocorticoid and loop diuretics (e.g. spironolactone andfurosemide), and this can explain why diuretic treatment becomesunsuccessful in some patients. In addition, the reduced cardiovascularresponsiveness to vasoconstriction perpetuates the relativeunder-filling of the effective arterial blood volume and this compoundsthe hypovolemic effects of diuretics (Salerno 2010). Iatrogenic factorsmay also contribute. These include the administration of nonsteroidalanti-inflammatory drugs which impair renal function by inhibiting thesynthesis of vasodilating prostaglandins, the administration ofangiotensin-I-converting enzyme inhibitors or angiotensin receptorantagonists, which can impair the renal blood perfusion and reduce theglomerular filtration rate (GFR) or the administration of nephrotoxicdrugs such as aminoglycosides. Finally, complications including fluidloss through vomiting, diarrhea or bleeding, or bacterial infectionssuch as spontaneous bacterial peritonitis, can intensify arterialvasodilatation and worsen the mismatch between the intravascular volumeand the vascular capacitance (Salerno 2010).

At present, the only curative intervention for RA is livertransplantation, but this option is not available for many patients fora variety of reasons including general medical condition and absence ofsuitable donor organs. Treatment options available to patients with RAinclude repeated large volume paracentesis (LVP), transjugularintrahepatic portosystemic shunt placement (TIPS), experimentalautomated low-flow pumps and the administration of vasoconstrictors(Piano 2018).

Paracentesis, the oldest treatment of ascites, is still the first-linetreatment for RA. LVP is effective especially in patients with tense(grade 3) ascites. Large-volume paracentesis (>5 L of ascites removed)combined with albumin i.v. infusion (6-8 g/L of ascites removed) andsaline as plasma expanders to prevent paracentesis induced circulatorydysfunction, is more effective than diuretics and causes fewercomplications (La Mura 2016, Pose 2017). It shortens hospital stay butit has no effect on mortality rate (Zhao 2018). The procedure should beavoided in patients with disseminated intravascular coagulation, andshould be performed with caution in patients with intra-abdominaladhesions or with a distended urinary bladder (Salerno 2010).Paracentesis is invasive and subjects a fragile population to therepeated risk of infection, an important factor the transformation of arelatively stable condition into acute decompensation and evenacute-on-chronic liver failure that has a 90-day mortality rate that canrange upwards of 75-80%.

The use of vasoconstrictor drugs can improve the underlying hemodynamicderangements that lead to ascites formation in cirrhosis, therebyreducing the activity of antinatriuretic factors. Data are available onthe use of vasoconstrictors (midodrine, clonidine, dopamine andterlipressin) with plasma expansion in patients with cirrhosis andascites. These drugs may improve renal function, urinary sodiumexcretion, and serum sodium levels in patients with advanced cirrhosisand hepatorenal syndrome (Pose 2017).

Positive effects of dopamine on effective renal plasma flow werereported in patients with RA, but with no difference in the changes ofblood urea nitrogen, creatinine, creatinine clearance, blood pressure,pulse rate, serum sodium, serum aldosterone and GFR (Lin 1998). Dopamineproduces natriuretic and positive inotropic effects when administeredintravenously, but it is not bioavailable when administered orally dueto high rates of metabolism in the gut and the liver. The dopamineprodrug docarpamine has been reported to be effective in a small cohortof RA patients (Funasaki 1999). None of the vasoconstrictor drugs havebeen approved for the treatment of ascites or RA in the U.S.

In view of the foregoing, there remains an urgent need for additionaltreatment options for RA and it is the aim of the present invention toprovide new therapeutic approaches for RA.

SUMMARY OF THE INVENTION

In one embodiment, the invention contemplates a method of treating apatient with ascites, comprising administering to said patient atherapeutically effective amount of docarpamine. Patients preferablyhave refractory ascites and are treated in a pulsatile manner, such thata treatment period during which the patient responds to treatment isfollowed by an off-treatment period during which the ascites worsensover time, which is then followed by another treatment period.Surprisingly, the off-treatment period typically shows a furtherreduction in the need for or the volume of large volume paracentesis andthis reduction persists for a month or more before ascites increases theneed for paracentesis and again warrants a return to drug treatment. Insome cases, the treatment period shows little or no reduction in theneed for or volume of paracentesis, yet a therapeutically meaningfuldecrease occurs during the off-treatment period.

Thus, treatment period are generally at least 30 days, but may be 60days, 90 days or even longer. The off-treatment period are similarly atleast 30 days, but may be 60 days, 90 days or more, guided by the rateof accumulation of ascites. Subsequent treatment and off-treatmentperiods are of similar duration. In certain embodiments, the duration ofone or more off-treatment periods exceeds the duration of the precedingtreatment period.

In some embodiments, instead of an off-treatment period, the dose ofdocarpamine is reduced relative to the preceding treatment period. Atypical dose reduction would be at least 50%, meaning a patient beingtreated, for example, at 1500 mg three times daily, would be treatedwith 750 mg or less three times daily in the next treatment period.Reductions may be 75%, 90% or more. As the need for or volume ofparacentesis increases during the reduced treatment period, the patientis returned to the higher dosing levels of the earlier treatment period.

Preferred daily doses are generally between 3000 and 6000 mg per day,generally administered 2-3 times per day. One dosing regimen involvestreatment with 1500 mg three times per day.

In some cases, prior to said administering, the patient is treated formore than 1 week with doses of furosemide >80 mg/day and/orspironolactone >100 mg/day or equivalent doses of an alternativeloop-acting and/or distal-acting diuretic. Further to this aspect of theinvention, it is further contemplated that the dose of diuretic agentsin the patient is not limited by diuretic-induced renal impairment. Inpreferred embodiments, the method further contemplates at least onesecond administration of docarpamine during which said patient is alsobeing treated with furosemide >80 mg/day and/or spironolactone >100mg/day.

Another embodiment of the invention relates to a method of treating apatient with ascites, comprising administering to said patient atherapeutically effective amount of docarpamine, wherein said ascites iscaused by liver cirrhosis due to alcohol or non-alcoholic fatty liverdisease.

Still another embodiment relates to a method of treating a patient withascites, comprising administering to said patient a therapeuticallyeffective amount of docarpamine, wherein said ascites is not caused bycirrhosis due to viral hepatitis or primary biliary cholangitis.

Yet another embodiment contemplates a method of treating a patient withascites, comprising administering to said patient a therapeuticallyeffective amount of docarpamine, wherein said patient has a serumaldosterone level exceeding 21 ng/dL (582.5 pmol/L) and or a serum reninconcentration exceeding 40 pg/mL (1.0 pmol/L).

A further embodiment of the invention envisions a method of treating apatient with ascites, comprising administering to said patient atherapeutically effective amount of docarpamine, wherein, prior totreatment, said patient required large volume paracentesis at a minimumof: (a) 3 times in 60 days, (b) 4 times in 90 days or (c) at least onceevery 30 days over a 90-day period.

Another embodiment of the invention involves a method of treating apatient with diuretic intractable ascites, comprising administering tosaid patient a therapeutically effective amount of docarpamine, whereinsaid a patient experienced one or more diuretic-induced complicationsselected from the group consisting of: diuretic-induced hepaticencephalopathy; diuretic-induced renal impairment; diuretic-inducedhyponatremia; and diuretic-induced hypokalemia.

Yet another embodiment contemplates a method of treating a patient withascites, comprising administering to said patient a therapeuticallyeffective amount of docarpamine, wherein said patient is unresponsive tosodium-restricted diet and intensive diuretic therapy.

Yet another embodiment relates to a method of treating a patientascites, comprising: administering to said patient a first amount ofdocarpamine; obtaining the concentration of dopamine in the blood, serumor plasma of said patient; and administering a second amount ofdocarpamine to said patient, wherein said second amount is selectedbased on the concentration of dopamine obtained.

A particularly preferred embodiment relates to a method of treating apatient with ascites, comprising administering to said patient a totaldaily dose of 4500 mg of docarpamine, administered 2-3 times per day toachieve the total daily dose. Pre-treatment, ascites patients arepreferably receiving regular large volume parascentesis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the treatment of a patient withascites. Ascites is commonly called excess abdominal fluid or abnormalaccumulation of fluid in the abdominal cavity. Many underlying diseasescan be responsible for causing ascites, including tuberculosis, kidneydisease, pancreatitis, and an underactive thyroid. Ascites may developin cancer when it affects the peritoneum, liver, lymphatic system,ovaries, breast, colon, stomach, pancreas, lung, or cervix. The primarycauses of ascites are heart failure, cirrhosis (cirrhotic ascites), andcancer (malignant ascites), with cirrhosis being responsible for morethan 80% of ascites cases.

In contrast to cirrhotic and other forms of ascites, malignant ascites(MA) occurs via a combination of altered vascular permeability andobstructed lymphatic drainage (Hodge and Badgwell, 2019). In MA, tumorcells lining the peritoneum secrete protein-rich fluid and extracellularenters the peritoneal cavity to maintain oncotic balance (Frick andSchölmerich, 2005). Cancers express factors that mediate increasedcapillary permeability, facilitating this fluid movement (Hodge andBadgwell 2019). A significant difference in MA relative to other ascitesis that tumor cells in the peritoneal cavity directly obstruct lymphaticchannels, leading to impaired uptake of fluid into the lymphatic system(Hodge and Badgwell 2019). Unlike other ascites etiologies, there is noantidiuretic effect at issue indicating that diuretics should beineffective, which they are, and that dopamine and, therefore dopamineprodrugs like docarpamine should likewise be ineffective.

Accordingly, patients treatable using the invention may, for example,have heart failure or cirrhosis or ascites due to other causes liketuberculosis, dialysis (nephrogenous), biliary dysfunction and fulminanthepatic failure, MA is excluded from the invention. Treatable patientspreferably have cirrhosis of the liver as the cause underlying theascites. Ascites in hepatocellular carcinoma is considered to be due tothe underlying cirrhosis, and not due to mechanisms associated with MAand so treating patients with ascites due to hepatocellular carcinoma isincluded in the invention since they are not understood to have MA.

Preferred embodiments of the invention pertain to treating cirrhoticascites. More preferred embodiments of the invention involve treating apatient with ascites, irrespective of cause, who is not effectivelymanaged such that the patient undergoes frequent large volumeparacentesis.

Preferred causes of cirrhotic ascites contemplated by the inventionresult from cirrhosis due to alcohol and cirrhosis due to non-alcoholicfatty liver disease. Certain embodiment of the invention are understoodto exclude ascites resulting from cirrhosis caused by viral hepatitis,such as hepatitis b or hepatitis c. Other embodiments exclude ascitesresulting from cirrhosis caused by primary biliary cholangitis.

Effectively managed, when referring to the ascites patient generallymeans the patient has been instructed to restrict sodium intake andmanagement using diuretic has proved effective. In such a patient wherediuretic treatment proves to be ineffective, the patient is notconsidered to be effectively managed. Diuretic treatment is ineffectiveeither because the patient is diuretic resistant or diureticintractable. A diuretic resistant patient does not respond to effectivedoses of diuretics. A diuretic intractable patient cannot be effectivelytreated with diuretics due to some safety or tolerability issue thatlimits the dose or the ability to use diuretics altogether.

Paracentesis is a procedure by which ascitic fluid is removed from theabdomen using a needle or catheter. Paracentesis may be performed fordiagnostic purposes, but in the present case it is done for therapeuticpurposes to remove fluid and alleviate the pressure created by the largevolume of fluid, which distends the abdomen and compresses internalorgans. Large volume paracentesis (LVP) generally involves the removalof 5 liters or more of ascitic fluid from the abdomen. In someinstances, it can involve the removal of 2, 3, 4, or 6, 7, 8, 9, 10 ormore liters of ascitic fluid from the abdomen. The word “frequent” whenused with LVP generally refers to at least one LVP at least every twomonths and generally at least every six weeks. More preferably, frequentLVP entails LVP at least once a month. In some cases, frequent LVPpatients treated according to the invention have LVP every 3, 2 or even1 week in certain cases. “Frequent” specifically contemplates LVP at aminimum of: (a) 3 times in 60 days, (b) 4 times in 90 days or (c) atleast once every 30 days over a 90-day period.

The treatment of a patient undergoing frequent LVP according to theinvention refers to the patient at baseline, before treatment isstarted. Once treatment according to the invention is started, thefrequency of LVP and/or the volume of ascites will decrease over timeand so any treatment after the initial treatment is still considered tobe a treatment of a patient undergoing frequent LVP because that was thepatient's condition at baseline.

Docarpamine is an orally-active prodrug of dopamine; dopamine is notorally bioavailable due to rapid metabolism in the small intestine andliver after administration (Merits 1973). Dopamine is a sympathomimeticamine vasopressor that is the naturally occurring immediate precursor ofnorepinephrine. Dopamine produces natriuretic and positive inotropiceffects when administered intravenously. It is indicated for thecorrection of hemodynamic imbalances present in the shock syndrome dueto myocardial infarction, trauma, endotoxic septicemia, open-heartsurgery, renal failure, and chronic cardiac decompensation as incongestive failure. Its use is approved when there is poor perfusion ofvital organs, low cardiac output and/or hypotension (FDA, dopaminelabel).

Docarpamine is not approved in the US, but it has been available inJapan since 1995 under the brand name Tanadopa by Mitsubishi TanabePharmaceutical Company. The drug is used to wean patients withcirculatory failure off of intravenous dopamine. Docarpamine is rapidlymetabolized to free dopamine in the small intestine and liver andresults in the detection of elevated circulating dopamine levels. Thestructure of docarpamine is provided below.

At low rates of infusion (0.5-2 mcg/kg/min) dopamine causes vasodilationthat is presumed to be due to a specific agonist action on dopaminereceptors (distinct from alpha-and beta-adrenoceptors) in the renal,mesenteric, coronary, and intracerebral vascular beds. The vasodilationin these vascular beds is accompanied by increased glomerular filtrationrate, renal blood flow, sodium excretion, and urine flow. Hypotensionsometimes occurs.

At intermediate rates of infusion (2-10 mcg/kg/min) dopamine acts tostimulate the beta1 adrenoceptors, resulting in improved myocardialcontractility, increased sino-atrial rate and enhanced impulseconduction in the heart. There is little, if any, stimulation of thebeta2-adrenoceptors (peripheral vasodilation). Dopamine causes lessincrease in myocardial oxygen consumption than isoproterenol, and itsuse is not usually associated with a tachyarrhythmia. Clinical studiesindicate that it usually increases systolic and pulse pressure witheither no effect or a slight increase in diastolic pressure. Blood flowto the peripheral vascular beds may decrease while mesenteric flowincreases due to increased cardiac output. Total peripheral resistance(alpha effects) at low and intermediate doses is usually unchanged.

At higher rates of infusion (10-20 mcg/kg/min) there is some effect onalpha-adrenoceptors, with consequent vasoconstrictor effects and a risein blood pressure. The vasoconstrictor effects are first seen in theskeletal muscle vascular beds, but with increasing doses, they are alsoevident in the renal and mesenteric vessels. At very high rates ofinfusion (above 20 mcg/kg/min), stimulation of alpha-adrenoceptorspredominates and vasoconstriction may compromise the circulation of thelimbs and override the dopaminergic effects of dopamine, reversing renaldilation and natriuresis.

In practicing the inventive methods, docarpamine is generallyadministered in order to target engagement of the renal dopaminereceptors, responsible for increased glomerular bloodflow and diuresis.Increases in cardiac output mediated by beta 1 adrenergic receptors mayalso be beneficial in terms of increasing renal perfusion and so theinventive methods contemplate dosing that may increase cardiac output.Generally, doses of docarpamine will avoid clinically observable (byincreases in blood pressure) systemic alpha adrenergic effects, thoughsubclinical effects are contemplated and may be beneficial. Accordingly,usually the inventive methods use doses that do not materially alter theblood pressure of the patient. The maximum target plasma levels of freedopamine will generally not exceed those obtained with a dopamineinfusion of about 10-15 mcg/kg/min. More typically, such target plasmalevels will not exceed those obtained with a dopamine infusion of about10 mcg/kg/min. In preferred embodiments, target plasma levels will be inthe range of those obtained with a dopamine infusion of about 2 to about7 mcg/kg/min and most preferably from about 2 to about 5 mcg/kg/min.

Some of the inventive methods involve treating a patient with at leastone dose of docarpamine, measuring the amount of free dopamine in theblood and then administering at least one additional dose of docarpaminethat is determined based on maintaining dopamine plasma levels withinthe foregoing target plasma levels. Typical target plasma levels fordopamine will be between 1 and 300 ng/ml. Preferable target plasmalevels will be between 10 and 150 ng/ml with more preferred targetplasma levels being from 20-110 ng/ml or 20-80 ng/ml. Most preferredtarget plasma levels are from 40-80 ng/ml.

Typical daily doses of docarpamine will not exceed 6,750 mg per day andgenerally will be between 750 mg and 5000 mg per day. While a totaldaily dose of 2250 mg is contemplated, 4500 mg per day is particularlypreferred. The total daily dose is generally administered in more thanone daily dose and usually 2-3 doses of equal amount per day comprisethe total daily dose. Dosing preferably continues for more than 7 daysand typically continues for at least one month. More preferably dosingcontinues for at least 3 months or at least 6 months.

Particularly preferred dosing regimens entail treating a patient withascites (preferably refractory ascites) in a pulsatile manner, such thattreatment ensues and is followed by an off-treatment period, after whichdrug is resumed. This may be repeated any number of times. The doseduring each treatment period may be the same or different as thetreatment period preceding the off-treatment period. The duration ofeach treatment period is sufficient to substantially reduce thefrequency of LVP and/or reduce the volume of ascites removed during LVP.A typical treatment period would be at least 2 weeks and generally atleast 4 weeks and may extend for 2, 3 or 4 months or even longer. Theduration of each off-treatment period is of sufficient duration suchthat the volume of ascites and/or frequency of LVP returns to at least50% of pre-treatment levels. Thus, the off period will generally be atleast 2 weeks and more typically 3 to 4 weeks, but it may extend 2, 3 or4 months or longer, depending on patient response and need to resumetherapy.

Dosing during treatment periods may be made with reference to theforegoing guidance. A preferred method entails administering 1000 to2000 mg of docarpamine three times per day for a total daily dose of3000-6000 mg, 1250 to 1750 mg of docarpamine three times per day(1750-5250 mg total per day) or 1400 to 1600 mg of docarpamine threetimes per day (4200-4800 mg per day total). The administration of 1500mg three times per day or a total of 4500 mg per day is most preferred.

The invention further contemplates the use of other oral prodrugs ofdopamine, which upon administration to the body are converted todopamine. An example of such oral prodrug of dopamine is 1-DOPA, alsoknown as levodopa or 1-3,4-dihydroxyphenylalanine. Unlike docarpamine,levodopa is not derivatized at the catechol moiety (the two —OH groupson the aromatic ring), but is derivatized as a simple peptide bond atthe amino group. The structure of levodopa ask compared to dopamine isas follows:

Generally, orally bioavailable prodrugs will be derivatized similarly todocarpamine and levodopa to product the amino group (preferably byforming a peptide bond) and/or one or both of the hydroxyl groups of thecatechol moiety, generally as an ester. One skilled in the art willreadily understand the types of modifications that can be made todopamine in order to create additional dopamine prodrugs. Dosing of suchadditional prodrugs may be guided by the same principles set out aboverelating to target plasma dopamine concentrations using methods wellknown to those skilled in the art. Dosing for levodopa in order toachieve such plasma dopamine concentrations will generally require atleast 1 gram per day and not more than 5 grams per day and preferablyfrom 2, 3 or 4 grams per day, most preferably 2-3 grams per day.

Grading Ascites

The methods of the invention involve treating patients with ascites,which are graded according to the following criteria:

Grade 1 ascites is mild and can be detected only by an examination suchas ultrasound;

Grade 2 ascites is moderate and evidenced by moderate distension of theabdomen, and is therefore readily detectable on physical examination;and

Grade 3 ascites is large with marked distension of the abdomen.

The inventive methods are particularly adapted to treating higher gradesof ascites, most particularly Grade 3 and sometimes Grade 2.

Refractory Ascites

The inventive methods are useful in the treatment of refractory ascites.There are a number of definitions of Refractory Ascites and thetreatment of patients that fall under one or more of these definitionsis hereby contemplated. Exemplary definitions have been provided by theAmerican Association for the Study of Liver Disease (AASLD), theEuropean Association for the Study of the Liver (EASL), theInternational Club for Ascites (ICA) and the Asia Pacific Associationfor the Study of the Liver (APASL).

As generally referred to herein, refractory ascites is defined asascites that does not resolve or that recurs shortly after therapeuticparacentesis, despite sodium restriction and diuretic treatment(Siqueira 2009). Refractory ascites includes two subgroups (EASL 2010):diuretic-resistant ascites and diuretic intractable ascites.Diuretic-resistant patients are those who fail to respond to intensivetreatment with diuretics. Diuretic-intractable patients are those whocould not tolerate an effective dose of diuretic.

Sodium restriction is the universally accepted first step in trying themanage ascites. Instructions are provided to patients regarding managingsodium intake, but this cannot be reasonably monitored by the physicianin an outpatient population. Accordingly, while patients are instructedin this regard, enforcement of sodium restriction is not a requirementfor regarding a patient as refractory; it is sufficient thatinstructions are given.

Widely considered the seminal work in refractory ascites and used as thefoundational definition for most others, including EASL, Arroyo (1996)defines refractory ascites as ascites that cannot be mobilized or theearly recurrence of which (i.e., after therapeutic paracentesis) cannotbe satisfactorily prevented by medical therapy. Refractory ascitesincludes both diuretic-resistant ascites and diuretic intractableascites. Diuretic-resistant ascites are ascites that cannot be mobilizedor the early occurrence of which cannot be prevented because of lack ofresponse to dietary sodium restriction and intensive diuretic treatment.Diuretic-intractable ascites are ascites that cannot be mobilized or theearly occurrence of which cannot be prevented because of the developmentof diuretic-induced complications that preclude the use of an effectivediuretic dosage.

According to the criteria of the International Ascites Club, refractory.ascites is defined as “ascites that cannot be mobilized or the earlyrecurrence of which (i.e., after LVP) cannot be satisfactorily preventedby medical therapy”

Consistent with Arroyo (1996), the following criteria were adopted bythe International Club of Ascites in defining diuretic resistant ascites(Moore 2003) and they are adopted for the purposes of the presentinvention:

-   -   1. “Intensive diuretic therapy” means spironolactone at 400        mg/day and furosemide at 160 mg/day for at least 1 week with a        salt-restricted diet (<5.2 g of salt/day);    -   2. “Lack of response” is defined as a mean weight loss of <0.8        kg over 4 days and a urinary sodium output less than the sodium        intake;    -   3. “Early recurrence” is defined as the reappearance of grade 2        or 3 ascites within 4 weeks of initial mobilization; and    -   4. “Diuretic-induced complications” include, diuretic-induced        hepatic encephalopathy, diuretic-induced renal impairment,        diuretic-induced hyponatremia, and diuretic-induced        hypokalaemia.

Diuretic-induced hepatic encephalopathy is defined as development ofencephalopathy without any other precipitating factor. Diuretic-inducedrenal impairment is defined as an increase in the serum creatinine levelof >100% to a value >2 mg/dL in patients with treatment-responsiveascites. Diuretic-induced hyponatremia is defined as a decrease in theserum sodium level of >10 mmol/L or a serum sodium level of <125 mmol/L.Diuretic-induced hypokalaemia or hyperkalaemia is defined as a change inserum potassium to <3 mmol/L or >6 mmol/L, despite appropriate measures.Each of the foregoing complications may be a factor in eliminatingdiuretic therapy or reducing diuretic doses to levels at which patientsare no longer effectively managed and, therefore, are deemed diureticintractable, one subtype of refractory ascites.

Accordingly, the treatment of patients with diuretic intractable ascitesis specifically contemplated. Specific embodiments of treating a patientwith intractable ascites include methods of treating a patient withdiuretic intractable ascites, comprising administering to said patient atherapeutically effective amount of docarpamine, wherein said a patientexperienced one or more diuretic-induced complications selected from thegroup consisting of: diuretic-induced hepatic encephalopathy;diuretic-induced renal impairment; diuretic-induced hyponatremia; ordiuretic-induced hypokalaemia.

The AASLD defines RA as fluid overload that 1) is unresponsive tosodium-restricted diet and high-dose diuretic treatment (400 mg/day ofspironolactone and 160 mg/day of furosemide), or 2) recurs rapidly aftertherapeutic paracentesis) (Runyon 2013).

One preferred embodiment of the invention relates to treating ascitespatients who have been treated with elevated doses of diuretics.Typically, patients will be treated with a combination of a loopdiuretic and a distal acting diuretic. Furosemide is a usual example ofthe loop diuretic and spironolactone is an example of a distal actingdiuretic. Such patients will have been treated with doses offurosemide >80 mg/day and/or spironolactone >100 mg/day or equivalentdoses of an alternative loop-acting and/or distal-acting diuretic for atleast one week preceding treatment with docarpamine in accordance withthe invention. Preferred ranges for furosemide are at least >80-100,100-150, 150-200, 200-250, 250-300, 300-350 and 350-400 mg per day.Preferred doses of spironolactone include >100-110, 110-120, 120-130,130-140, 140-150 and 150-160 mg/day. Equivalent doses of alternativeloop diuretics and distal acting diuretics may be determined by theskilled person and also applied to the inventive methods. Inparticularly preferred embodiments, at least one dose of docarpaminewith be administered while the patient is one such elevated doses of oneor more diuretics.

In other embodiments, patients are also treated with other vasoactivesubstances. In some embodiments the other vasoactive substances areagonists of the alpha 1 adrenergic receptors. Alpha 1 adrenergicreceptor agonists include methoxamine, midodrine, metaraminol,phenylephrine and amidephrine, with midodrine being a particularlypreferred other vasoactive substance. In other embodiments, the othervasoactive substances include vasopressin (antidiuretic hormone) andvasopressin analogues. Vasopressin analogues include desmopressin andterlipressin. Other vasoactive substances can also include somatostatinanalogs, such as octreotide.

In certain embodiments, patients treated in accordance with theinvention will have a certain minimum level of kidney function. Kidneyfunction is routinely assessed using creatinine—higher creatinine levelsare indicative or reduced kidney function. Normal creatinine levels inthe blood are typically between 0.5 and 1.2 milligrams per deciliter. Inmany cases a patient will have a serum creatinine level of <2 mg/dL. Inother cases a patient will have serum creatinine levels of <1.5 mg/dL.In still other cases a patient will have serum creatinine levels of <1mg/dL.

It is contemplated that cirrhotic patients with ascites will have analtered renin-angiotensin-aldosterone system and, without being held toa particular mechanism of action, that docarpamine treatment of asciteswill be more effective in patients with elevated renin and/or elevatedaldosterone levels. Thus, some embodiments of the invention relate totreating patients having an aldosterone level exceeding 21 ng/dL (582.5pmol/L) and/or a serum renin concentration exceeding 40 pg/mL (1.0pmol/L).

The invention contemplates the treatment of refractory ascites patientswho have low urinary sodium excretion even while on diuretic therapy.Normal ranges are 40-220 mEq/day (mmol/day) and patients treatedaccording to the invention will typically have a total daily (ie, 24hour) sodium excretion of less than 40 mEq day. In some embodiments,sodium excretion in the presence of diuretics (eg, spironolactone andfurosemide) will be less than 30 mEq/day, less than 20 mEq/day, lessthan 10 mEq/day or even less than 5 mEq/day. Spot urine tests in suchpatients will yield sodium of less than 20 mEq/L and more generally lessthan 15 mEq/L, less than 10 mEq/L, less than 5 mEq/L or even less than 1mEq/L, despite treatment with diuretics. In some cases spot urine sodiumwill be less than 0.1 mEq/L, less than 0.01 mEq/L or even undetectable.Spot urinary Na/K ratio will be less than 1 and sodium excretion inresponse to a single intravenous dose of 80 mg furosemide will be lessthan 50 mEq/8 hours.

Some methods contemplate treating a patient with diuretic intractableascites by administering to said patient a therapeutically effectiveamount of docarpamine, wherein said a patient experienced one or morediuretic-induced complications selected from the group consisting of:diuretic-induced hepatic encephalopathy; diuretic-induced renalimpairment; diuretic-induced hyponatremia; and diuretic-inducedhypokalemia. Methods are further understood to involve treating apatient with ascites by administering to said patient a therapeuticallyeffective amount of docarpamine, wherein said patient is unresponsive tosodium-restricted diet and intensive diuretic therapy.

Certain other methods of treating a patient with ascites entail:administering to said patient a first amount of docarpamine; obtainingthe concentration of dopamine in the blood, serum or plasma of saidpatient; and administering a second amount of docarpamine to saidpatient, wherein said second amount is selected based on theconcentration of dopamine obtained.

In other methods, a patient with ascites is treated by administering tosaid patient a therapeutically effective amount of docarpamine, whereinprior to treatment said patient has a 24-hour urinary sodium excretionof less than 40 mEq during treatment with one or more diuretic agents.In some methods a patient with ascites is treated with a dose ofdocarpamine exceeding 2250 mg per day.

Embodiments of the present disclosure can be further defined byreference to the following examples. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, can be practiced without departing from the scope of thepresent disclosure. As used herein and in the appended claims, thesingular forms “a,” “or,” and “the” include plural referents unless thecontext clearly dictates otherwise.

Example 1: Clinical Study Design

An open-label, single-arm study in which each subject serves as his/herown control is conducted. The study assesses the effect of DCP treatmenton ascites formation in cirrhotic subjects with RA, by examining thefrequency of LVP and the volume of ascitic fluid drained. All subjectsparticipate in a 90-day open-label treatment period. One group receives750 mg docarpamine 3 times per day (total daily dose of 2250 mg) and asecond group receives 1500 mg docarpamine 3 times per day (total dailydose of 4500 mg), followed by a 90-day follow-up. Ascites history(relevant medications, LVP dates, and volume of drained fluid) for the90 days prior to treatment and the 90 days after treatment are collectedand used for comparison with on-treatment frequency and volume.

Study Population

The study population consists of cirrhotic patients between 18 and 70years of age, inclusive, with refractory ascites, subject to thefollowing inclusion and exclusion criteria.

Inclusion Criteria

-   -   Patients 18 years to 70 years of age.    -   Documented cirrhosis of the liver.    -   Refractory ascites, defined as ascites not manageable with        diuretics and diet restriction, managed with periodic large        volume therapeutic paracentesis.    -   Patients must have therapeutic paracenteses in the 3 days prior        to enrollment and a documented minimum of 3 additional        therapeutic paracenteses in the 90 days prior to enrollment,        with at least 1 every 30 days.    -   Outpatient, with expected survival of at least 6 months.    -   Willing and able to complete an informed consent form.

Exclusion Criteria

-   -   Ascites due to any cause other than cirrhosis such as malignant        ascites.    -   Existing or planned placement of Transjugular Intrahepatic        Portosystemic Shunt or other surgical shunts.    -   Active bacterial infection.    -   Scheduled organ transplantation within the next 6 months.    -   Change in diuretics schedule within 60 days prior to initiation        of treatment.    -   Model for End-stage Liver Disease-sodium Score of >25.    -   Serum creatinine >2 mg/dL.    -   Serum bilirubin >5 mg/dL.    -   International Normalized Ratio >1.5.    -   Hepatocellular Carcinoma Barcelona Classification of Liver        Cancer stage C or above.    -   Current or recent (within 3 months of consent) renal dialysis.    -   Hepatic encephalopathy grade 3 or 4.    -   Pheochromocytoma or hypertrophic obstructive cardiomyopathy.    -   Current or recent treatment (within 7 days) with octreotide,        midodrine, vasopressin, dopamine or other vasopressors.    -   Current or recent treatment (within 21 days) with monoamine        oxidase inhibitors, tricyclic antidepressants, phenytoin,        haloperidol or haloperidol-like drugs, or phenothiazines such as        prochlorperazine.    -   Episode of spontaneous bacterial peritonitis or gastrointestinal        hemorrhage, or any acute decompensation within 30 days of        enrollment.    -   Severe cardiovascular disease such as congestive heart failure,        advanced arteriosclerosis, coronary insufficiency,        tachyarrhythmia, or uncontrolled hypertension above 160/100.    -   Known or suspected extra-hepatic malignancy (other than skin        cancer and in-situ cancers), unless adequately treated.    -   Pregnant females, females anticipating pregnancy during study        period, or breastfeeding.    -   Known allergy or hypersensitivity to dopamine or docarpamine.    -   Any severe comorbidity that in the opinion of the Investigator        would disallow safe participation in the trial.    -   Participation in other clinical research studies involving the        evaluation of other investigational drugs or devices within 90        days of consent.

Results

Following 90 days for treatment the following effects are observed, butonly in the high dose (4500 mg per day group). Some patients do notrequire LVP for more than one month and others do not require LVP formore than two months. Overall, both the frequency of LVP and the volumeof ascites removed over 90 days is reduced by more than half on average.It is surprisingly observed that greater decreases in frequency andvolume of LVP occur once a patient stops treatment and the decreasepersists for one or more months before beginning to increase again.Increased sodium excretion and other markers of improved renal functionrespond positively. Most patient go from 500-1000 ml urinary output to1500-2000 ml or more. Renin and/or aldosterone levels are reduced, insome cases to normal, in many patients. It is concluded that the optimaldose of docarpamine is 4500 mg per day.

What is claimed is:
 1. A method of treating a patient with refractoryascites, comprising (i) administering to said patient a therapeuticallyeffective amount of docarpamine during a first period, (ii) followingsaid first period, reducing the amount of docarpamine administrated tosaid patient for a second period, and (iii) following said secondperiod, increasing the amount of docarpamine administered to saidpatient for a third period.
 2. A method according to claim 1, whereinthe daily dose of docarpamine administered in said third period is thesame as the daily dose of docarpamine administered in said first period.3. A method according to claim 1, wherein said patient is notadministered docarpamine during said second period.
 4. A methodaccording to claim 1, wherein said second period exceeds two weeks.
 5. Amethod according to claim 1, wherein said second period is of the sameduration or longer than said first period.
 6. A method according toclaim 1, wherein said second period begins when the patient does notrequire large volume paracentesis for at least six weeks.
 7. A methodaccording to claim 1, wherein, prior to said first period, the patientis treated for more than 1 week with doses of furosemide >80 mg/dayand/or spironolactone >100 mg/day or equivalent doses of an alternativeloop-acting and/or distal-acting diuretic.
 8. A method according toclaim 4 wherein the dose of diuretic agents is not limited bydiuretic-induced renal impairment.
 9. The method according to claim 1,during at least on period said patient is also being treated withfurosemide >80 mg/day and/or spironolactone >100 mg/day.
 10. A methodaccording to claim 1, wherein said ascites is caused by liver cirrhosisdue to alcohol or non-alcoholic fatty liver disease.
 11. A methodaccording to claim 1, wherein said ascites is not caused by cirrhosisdue to viral hepatitis or primary biliary cholangitis.
 12. A methodaccording to claim 1, wherein said patient has a serum aldosterone levelexceeding 21 ng/dL (582.5 pmol/L) and or a serum renin concentrationexceeding 40 pg/mL (1.0 pmol/L).
 13. A method according to claim 1,wherein, prior to said first period, said patient required large volumeparacentesis at a minimum of: (a) 3 times in 60 days, (b) 4 times in 90days or (c) at least once every 30 days over a 90-day period.
 14. Amethod according to claim 12, wherein said patient is treated with adocarpamine dose of 4500 mg per day.
 15. A method according to claim 13,wherein said docarpamine dose is administered in 2 or 3 portions perday.
 16. A method according to claim 12, wherein said patient, prior tobeginning treatment, is undergoing large volume paracentesis at leastonce every two months.
 17. A method according to claim 15, wherein saidpatient, prior to beginning treatment, is undergoing large volumeparacentesis at least once per month.
 18. A method according to claim12, wherein said patient, prior to beginning treatment, is having anaverage of at least 2 liters of fluid per month being removed by largevolume paracentesis.